Liankun Ai,
Ibrahim Yusuf Ajibola and
Baolin Li*
School of Chemical Sciences, University of Chinese Academy of Sciences, Beijing 100049, P. R. China. E-mail: libl@ucas.ac.cn
First published on 10th November 2021
An efficient method to synthesize benzothieno[3,2-b]benzofurans via intramolecular dehydrogenative C–H/O–H coupling has been developed. Good to excellent yields (64–91%) could be obtained no matter if the substituted group is electron-donating or electron-withdrawing. Notably, three-to-six fused ring thienofuran compounds could be constructed using this method. A reaction mechanism study showed that 1,1-diphenylethylene can completely inhibit the reaction. Therefore, it is a radical pathway initiated by single electron transfer between the hydroxyl of the substrate and the copper catalyst.
As we all know, an oxygen atom and a sulfur atom have a similar valence electron configuration; the difference is that the oxygen atom has a smaller atomic radius and a larger electronegativity. The smaller atomic radius of the oxygen atom may decrease the intermolecular distance and increase the intermolecular π-orbital overlap, which facilitates the charge transport property in the solid state. Thus, furan-fused π-conjugated molecules are being viewed as very promising materials in organic electronics.9,15–21 BTBF motif is believed to be a promising candidate for material applications as it possesses a similar structure and energy profile with those of BTBT according to the density functional theory (DFT) calculations.13 However, there are only a few examples for BTBFs used in optoelectronic devices.13,22–24 One major problem restraining the applications of BTBFs can be attributed to the lack of facile synthetic routes toward these oxygen-containing heteroacenes as oxygen atom has only one valence state of −2 to construct the furan ring. Thus, developing a new and efficient synthetic method toward BTBFs is paramount for their material applications.
The synthesis of BTBF was firstly realized by Aitken group using flash vacuum pyrolysis of 2-methylthiophenyl substituted phosphorus ylides in 1995 (Scheme 1a).25,26 By the reaction of benzothieno[3,2-b]furan with substituted dienes, Svoboda group synthesized tetrahydro[1]benzothieno[3,2-b][1]benzofuran derivatives which were transformed into BTBFs by dehydrogenative aromatization (Scheme 1b).27 A Pd-catalyzed intramolecular oxidative C–H/C–H coupling of 3-aryloxybenzo[b]thiophenes was independently reported by Kuninobu28 and Miura group29 in 2015 (Scheme 1c). Then a Cu-catalyzed Ullmann-type intramolecular C–O bond coupling reaction toward BTBFs was developed by our group and coworkers (Scheme 1d).13 Later on, You group used a similar strategy to synthesize these compounds.30 Recently, Mitsudo group have reported an electrochemical synthesis of this type of compounds from 2-(benzo[b]furan-2-yl)benzenethiol via a dehydrogenative C–H/S–H coupling (Scheme 1e).31 Most recently, John group have developed a mild metal-free synthetic route toward BTBFs by the annulation of 3-nitrobenzothiophene with phenols (Scheme 1f).32 However, all these methods required metal catalysts or harsh conditions, and multistep transformations for the synthesis of BTBFs with limited scopes.
The construction of furan-fused π-conjugated molecules through dehydrogenative C–H/O–H coupling has been studied in the past decade. Liu33 and Yoshikai group34 independently reported the Pd-catalyzed synthesis of dibenzofuran derivatives through dehydrogenative C–H/O–H coupling. Zhu group discovered that copper catalysts could also promote dehydrogenative etherification to form dibenzofurans.35,36 Hong et al. reported the synthesis of heterocyclic-fused benzofurans via dehydrogenative C–H/O–H coupling of flavones and coumarins.37 Shimada and coworkers reported that dual C–H/O–H coupling of binaphthols occurred to furnish peri-xanthenoxanthenes.38 To be noted, the products by the methods mentioned above have been limited to aryl ethers and lactones.
Inspired by the results mentioned above, we hypothesized that BTBFs could be constructed via intramolecular dehydrogenative C–H/O–H coupling reaction. Herein, due to our continuing interest in Cu-catalyzed synthesis of furan-fused π-conjugated molecules,13–15 we have been motivated to investigate the construction of BTBFs via dehydrogenative C–H/O–H coupling reaction as shown in Scheme 1g. The advantages of this novel approach compared with our previous strategy (Scheme 1d) are as followed: (1) the bromination of β-position of thiophene is unnecessary which simplifies the reaction; (2) the debromination side reaction which was found in our previous strategy could be avoided which helps to improve the reaction yield.
Entry | [Pd]/[Cu] | Ligand | Base | Oxidant | Solvent | Yieldb (%) |
---|---|---|---|---|---|---|
a Reaction conditions: 1a (0.20 mmol), Pd(OAc)2 or Cu catalyst (0.2–3 equiv., 0.04–0.6 mmol), ligand (0.4 equiv., 0.08 mmol), base (1 equiv., 0.20 mmol), oxidant (for entries 2–4, 3 equiv., 0.60 mmol), solvent (4 mL), 110 °C, the reactions were performed under nitrogen if the oxidant is neither air nor oxygen.b Determined by 1 H NMR with 1,3,5-trimethoxybenzene as an internal standard.c Isolated yields. | ||||||
1 | Pd(OAc)2, 0.2 equiv. | IPr | Cs2CO3 | Air | Toluene | 0 |
2 | Pd(OAc)2, 0.2 equiv. | IPr | Cs2CO3 | Cu(OAc)2 | Toluene | 8 |
3 | Pd(OAc)2, 0.2 equiv. | Pyridine | Cs2CO3 | Cu(OAc)2 | Toluene | 11 |
4 | Pd(OAc)2, 0.2 equiv. | Pyridine | Cs2CO3 | Cu(OAc)2 | Pyridine | 21 |
5 | Cu(OAc)2, 0.2 equiv. | o-Phen | Cs2CO3 | Air | Pyridine | Trace |
6 | Cu(OAc)2, 0.2 equiv. | 2,2′-Bipyridine | Cs2CO3 | Air | Pyridine | Trace |
7 | Cu(OAc)2, 0.2 equiv. | — | Cs2CO3 | Air | Pyridine | Trace |
8 | Cu(OAc)2, 0.5 equiv. | — | Cs2CO3 | Air | Pyridine | 32 |
9 | Cu(OAc)2, 1 equiv. | — | Cs2CO3 | Air | Pyridine | 47 |
10 | Cu(OAc)2, 3 equiv. | — | Cs2CO3 | Air | Pyridine | 51 |
11 | Cu(OAc)2, 3 equiv. | — | Cs2CO3 | O2 | Pyridine | 35 |
12 | Cu(OAc)2, 3 equiv. | — | Cs2CO3 | — | Pyridine | 90 (86)c |
13 | Cu(OAc)2·H2O, 3 equiv. | — | Cs2CO3 | — | Pyridine | 64 |
14 | CuOAc, 3 equiv. | — | Cs2CO3 | — | Pyridine | 51 |
15 | Cu2S, 3 equiv. | — | Cs2CO3 | — | Pyridine | 7 |
16 | CuS, 3 equiv. | — | Cs2CO3 | — | Pyridine | Trace |
17 | CuCl, 3 equiv. | — | Cs2CO3 | — | Pyridine | 0 |
18 | CuCl2, 3 equiv. | — | Cs2CO3 | — | Pyridine | 0 |
19 | CuBr2, 3 equiv. | — | Cs2CO3 | — | Pyridine | 0 |
20 | CuI, 3 equiv. | — | Cs2CO3 | — | Pyridine | 0 |
21 | Cu(OAc)2, 3 equiv. | — | K2CO3 | — | Pyridine | 34 |
22 | Cu(OAc)2, 3 equiv. | — | NaOAc | — | Pyridine | 59 |
23 | Cu(OAc)2, 3 equiv. | — | — | — | Pyridine | 20 |
24 | Cu(OAc)2, 3 equiv. | Pyridine | Cs2CO3 | — | Toluene | 30 |
25 | Cu(OAc)2, 3 equiv. | — | Cs2CO3 | — | DMSO | 44 |
26 | Cu(OAc)2, 3 equiv. | — | Cs2CO3 | — | DMF | Trace |
27 | Cu(OAc)2, 3 equiv. | — | Cs2CO3 | — | Isopropanol | 0 |
28 | Cu(OAc)2, 3 equiv. | — | Cs2CO3 | — | t-Butanol | 0 |
To clarify the reaction scope, we next devoted our efforts to test a variety of 2-(benzo-[b]thiophen-2-yl)phenol derivatives 1 under the optimized reaction conditions (Scheme 2). Firstly, we selected o-, m- or p-substituted 2-(benzo[b]-thiophen-2-yl)phenols as the substrates, and found that all the yields (2b–k, 64–91%) were good to excellent no matter the substituted group is electron-donating or electron-withdrawing. The substrates with weak electron-donating groups such as alkyl chains afforded very high yields (2b–d, 85–91%), however, the substrate with a strong electron-donating group such as methoxy group gave comparably low yield (2e, 64%). For a specific substituent, the substituting position affects the yield: p-fluoro substituted BTBF (2f, 85%) > m-substituted BTBF (2g, 78%) > o-substituted BTBF (2h, 68%), probably due to the different steric hindrance of fluoro substituent in different position.
Scheme 2 Reaction scope for the intramolecular dehydrogenative C–O coupling reaction under optimized conditions. a The yields in the parenthesis reported in our previous paper are shown for comparison with this work.13 |
Next, we tested phenols with substituted benzo[b]thiophene moieties, and also got excellent yields (2l–2m, 81–91%). For more π-extended 3-(benzo[b]thiophen-2-yl)naphthalen-2-ol as the substrate, the yield only slightly dropped, affording benzo[4,5]thieno[3,2-b]naphtho[2,3-d]furan (2n, BTNF, 63%). Although substrates having a thiophene unit (1o) or bithiophene unit (1p) could also be used in this reaction, the yields significantly dropped (2o, 45%; 2p, 40%), probably because the cation intermediate could not be effectively stabilized without the resonance with phenyl group (see proposed mechanism, vide infra). Thus, not surprisingly, the yield of 2q is even lower (16%) because it is obtained via two subsequent intramolecular dehydrogenative C–H/O–H couplings. Thus, three-to-six fused ring thienofuran compounds could be constructed. Notably, the yields of BTBFs are comparable or even higher than those reported in our previous paper (2c 91% vs. 87%, 2f 85% vs. 90%, 2l 81% vs. 66%, and 2m 91% vs. 81%),13 indicating advantage of the new synthetic approach.
Subsequently, we investigated the gram-scale synthesis of copper-mediated construction of benzothieno[3,2-b]benzofurans by intramolecular dehydrogenative C–O coupling reaction. 2-(Benzo-[b]thiophen-2-yl)phenol derivatives 1a and 1f (6 mmol) reacted under the optimised reaction conditions, affording their corresponding benzothieno[3,2-b]benzofurans 2a and 2f in high yields which are comparable with those obtained on a 0.2 mmol scale (Fig. 1).
To gain insight into the reaction mechanism, some deuterium-labeling experiments were conducted with deuterated 2-(benzo[b]thiophen-2-yl-3-d)phenol (1a-D) (Scheme 3). The rate measurements revealed kinetic isotope effects (KIEs) of 1.1, indicating that the C3–H bond cleavage is not necessarily involved in the turnover limiting step of the reactions. The deuterated percentage in residual compounds did not change obviously, which indicated that cleavage of C3–D or C3–H bond is irreversible and thus phenolic hydroxyl played an important role in C–H functionalization.37
Scheme 3 Kinetic isotope effect study. Reaction conditions: 1a and 1a-D (0.20 mmol), Cu catalyst (3 equiv., 0.6 mmol), base (1 equiv., 0.20 mmol), solvent (4 mL), 110 °C, 6 h under nitrogen. |
A radical inhibition test was carried out in order to gain insight into whether the reaction proceeded through radical intermediates (Scheme 4). We selected 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), butylated hydroxytoluene (BHT) and 1,1-diphenylethylene as the radical scavenger which are widely used in free radical capture experiments.39–43 It is found that the NMR yield dropped to 10% in the presence of TEMPO, and 55% of the starting material was still left. In the presence of BHT, the yield of the target product dropped to 20%. While the desired cyclization reaction was completely inhibited by 1,1-diphenylethylene. These results clearly indicate that the reaction pathway is a radical mechanism. Unfortunately, all the efforts to detect the adducts between the substrate and radical intermediates failed.
Although the detailed mechanism remains to be elucidated, a possible reaction pathway is proposed based on the above observations (Scheme 5). At first, 1a reacts with a base, generating anionic intermediate A. Then phenoxy radical B is produced via single electron transfer with Cu(OAc)2, followed by intramolecular C–O cyclization to generate radical intermediate C. Afterward, cationic intermediate D is formed by oxidation with Cu(OAc)2. Finally, the target product 2a is obtained by the abstraction of a proton with the base.
Footnote |
† Electronic supplementary information (ESI) available: Experimental procedures, characterization data, UV-vis absorption spectra, emission spectra, crystal structure data, and other additional information. See DOI: 10.1039/d1ra06985c |
This journal is © The Royal Society of Chemistry 2021 |